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Optimization of the Lead Compound NVP-BHG712 as a Colorectal Cancer Inhibitor.

Authors :: Tröster A
DiPrima M
Jores N
Kudlinzki D
Sreeramulu S
Gande SL
Linhard V
Ludig D
Schug A
Saxena K
Reinecke M
Heinzlmeir S
Leisegang MS
Wollenhaupt J
Lennartz F
Weiss MS
Kuster B
Tosato G
Schwalbe H
Source :: Chemistry (Weinheim an der Bergstrasse, Germany) [Chemistry] 2023 Apr 21; Vol. 29 (23), pp. e202203967. Date of Electronic Publication: 2023 Mar 22.
Publication Year :: 2023
Abstract: The ephrin type-A receptor 2 (EPHA2) kinase belongs to the largest family of receptor tyrosine kinases. There are several indications of an involvement of EPHA2 in the development of infectious diseases and cancer. Despite pharmacological potential, EPHA2 is an under-examined target protein. In this study, we synthesized a series of derivatives of the inhibitor NVP-BHG712 and triazine-based compounds. These compounds were evaluated to determine their potential as kinase inhibitors of EPHA2, including elucidation of their binding mode (X-ray crystallography), affinity (microscale thermophoresis), and selectivity (Kinobeads assay). Eight inhibitors showed affinities in the low-nanomolar regime (K <subscript>D</subscript> <10 nM). Testing in up to seven colon cancer cell lines that express EPHA2 reveals that several derivatives feature promising effects for the control of human colon carcinoma. Thus, we have developed a set of powerful tool compounds for fundamental new research on the interplay of EPH receptors in a cellular context.<br /> (© 2023 The Authors. Chemistry - A European Journal published by Wiley-VCH GmbH.)